Flavone acetic acid (FAA, Scheme 1) is a synthetic flavone with a unique pattern of antitumor activity. 
Unlike conventional antitumor agents, it causes rapid tumor necrosis with little resultant toxicity in normal tissues. FAA has demonstrated excellent activity against marine colon adenocarcinoma 38 and a broad spectrum of slow-growing solid tumors that are usually insensitive to most cytotoxic drugs (J. Plowman, et al., Cancer Treatment Reports 1986, 70, 631; G. Atassi et al., Eur. J. Med. Chem. Chim. Ther. 1995, 20, 393). In contrast to its solid tumor activity, FAA shows poor activity against murine leukemia cell lines (P388 and L1210). Because of its unique pre-clinical solid tumor activity, FAA has been evaluated in clinical trials (M. Bibby and J. Double, J. A. Anti-Cancer Drugs 1993, 4, 3). FAA's precise mechanism of anticancer action in experimental animals is poorly understood (S. Harris, et al., Biochem. & Biophy. Res. Commun.. 1997, 235, 509; J. Murray et al., Eur. J. Cancer. 1991, 27, 765), but undoubtedly is novel. Modification of FAA is continuing (P. Valenti et al., Anti-Cancer Drug Design. 1996, 11, 243).
In previous studies, numerous substituted 2-phenyl-4-quinolones were synthesized and evaluated for antimitotic and antitumor activities. Most compounds in this series showed promising in vitro activity in the NCI's human tumor cell lines (HTCL) assay with GI50 values in the low micromolar to nanomolar concentration range. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization (S. Kuo et al., J. Med. Chem. 1993, 36, 1146; L. Li et al., J. Med. Chem. 1994, 37, 3400; L. Li et al., J. Med. Chem. 1994, 37, 1126; Y. Xia et al., J. Med. Chem. 1998, 41, 1155). Thirteen compounds in this series have been selected for in vivo xenograft testing, and to date, compound 1 (NSC 656158) is active in vivo. In the xenograft ovarian OVCAR-3 model, treated mice demonstrated a 130% increase in life span.